CS196644B1 - 2-substituted derivatives of ergoline - Google Patents

Description

The invention relates to 2-substitution derivatives of ergoline-I, formula I, defined below for R ¹ and R ^2, pharmaceutically acceptable salts thereof and a process for producing thereof.

In formula (I), R ¹ is 1,3-dithiolan-2-yl or methyl and R ² is alkoxy, straight or branched (C 1 -C 4) alkyl, or amino. :

. The compounds of formula (I) showed a significant inhibitory effect on the secretion of adenohypophyseal prolactin in experimental animals in the bioassay, resulting in, for example, an antinidative effect in rats. The mentioned effect in rats (Wistar Konárovice) is significantly applied at doses of 0.5 to 5.0 mg of substance / kg administered orally

5th day after animal copulation. A particularly pronounced antinidant effect at 0.5 mg / kg has been found, for example, in the form of an aqueous solution of base tartrate in the case of D-2,6-dimethyl-8-ergolin-1-ylacetic acid amide, administered under the above conditions. The potency of the antinidative effect of said compound is comparable to that of D-6-methyl-8-cyanomethylergoline-I (see, e.g., U.S. Pat. No. 132,156).

Compounds of formula I wherein R ¹ and R ² are as defined above are prepared by a sequence of reactions wherein D-6-methyl-8-ergolin-1-ylacetic esters, preferably readily accessible methyl ester, are used as starting materials. No. 132156 and No. 171570 respectively) which condense with 2-alkoxy-1,3-dithiolane prepared in situ in the reaction medium by reacting ethanedithiol with ethyl formate or methyl formate under the catalytic action of a Lewis acid , e.g. titanium tetrachloride, in an indifferent medium. A mixture of chloroform and ethyl formate has proven to be a suitable inert medium. Condensation is carried out at 20-25 ° C to give D-6-methyl-2- (1,3-dithlolan-2-yl) -8-ergolin-1-ylacetic acid esters.

D-6-methyl-2- (1,3-dithiolan-2-yl) -8-ergolin-1-ylacetic esters are converted to D-2,6-dimethyl-8-ergolin-1-ylacetic esters without pressure by reductive desulfurization, by treatment with Raney nickel in the polar medium, preferably in a medium of dimethylformamide and acetone. Reductive desulfurization proceeds with good yield already at 20-25 ° C.

In the next step, the D-2,6-dimethyl-8-ergolin-1-yl-acetic acid esters are converted to the corresponding amide by a conventional method of hydrazinolyl ester to hydrazide followed by reductive de-amination of hydrazide with Raney nickel in an alcoholic medium. Because of the simplicity and good yield of the reaction, this method is preferred over other methods used to synthesize amides in ergot alkaloid chemistry.

The reaction mixture from various stages of preparing compounds of formula I having the above meanings of R ¹ and R ² were processed in the usual conventional procedures known for the particular type of reaction. The crude products were purified by silica gel column chromatography and crystallization of the combined uniform fractions (see Examples). ¹ ·

According to the invention compounds of formula I wherein ^R1 represents a l, 3-dithiolane-2-yl group and R ² an alkoxy group having a linear or branched chain alkyl containing I to 4 carbon eTOM, prepared from the ester of D-6-methyl-8 -ergol-1-yl acetic acid, preferably methyl ester, by reaction with 1 to 2 mol equivalents of ethanedithiol and at least 2 mol equivalents of ethyl formate, preferably with an excess thereof, with a catalytic effect of 2 to 4 mol equivalents of titanium tetrachloride; ° C to the boiling point of the reaction mixture, preferably at 20 to 25 ° C, for 1 to 7 days, after which the reaction mixture is worked up, after deactivation of the catalyst and alkalinization, in a conventional manner, for example by removing the base in a suitable solvent and purifying the substance by chromatography or by crystallization.

According to the invention, compounds of the formula I in which R @ ¹ is methyl and R @ ² alkoxy, with a linear or branched chain containing 1-4 carbon atoms, are prepared from esters of D-6-methyl-2- (1,3-dithiol) -an-2-yl) -8-ergolin-1-yl acetate, reducing desulfurization of Raney nickel slurry in polar medium, preferably dimethylformamide / acetone, at 20-25 ° C, for up to 24 hours, preferably 3 hours After the reaction mixture is worked up in the usual manner, for example after separating the Raney nickel suspension and distilling off the acetone and stirring the residue in water, the precipitate is filtered off with suction and crystallized.

The compounds of formula I wherein R ¹ denotes methyl and R ² represents amino, according to the invention is prepared from the ester of D-2,6-dimethyl-ergoline-8-I-ylacetic acid by reaction with an excess of hydrazine hydrate, at a temperature · 150-160 ° C under nitrogen for 1 h and by reductive deamination of the resulting D-2,6-dimethyl-8-ergolin-II acid hydrazide 4 · ·. ·. · -

The ethyl acetate slurries of Raney nickel in ethanol were reacted for 2 hours at the boiling point of the reaction mixture, after which the reaction mixture was worked up in the usual manner.

Compounds of formula I having the above meanings of R ¹ and R ² are transformed in pharmaceutically acceptable salts by treatment with organic or inorganic acids such as; in the environment of lower alcohols such as methanol or ethanol. Of the inorganic acids, sulfuric, hydrochloric, and organic tartaric, maleic, methane and ethanesulfonic acids are suitable for this purpose. Particularly suitable salts suitable for pharmacological purposes. are maleates and tartrates of bases.

In the examples, the specific rotation values of the compounds were determined for bases in pyridine and for salts in methanol, and refer to solvent-free substances. Temperature values are expressed in ° C.

Examples

Example 1

D-6-Methyl-2- (1,3-dithiolan-2-yl) -8-ergolin-1-ylacetic acid methyl ester

To a solution of 1.85 g (6 mmol) of methyl D-6-methyl-8-ergolin-1-ylacetic acid in a mixture of 60 ml of chloroform and 20 ml of ethyl formate was added 1.13 g (12 mmol) of ethanedithiol and solution 4, 55 g (24 mmol) of titanium tetrachloride in 30 ml of chloroform. After 96 hours of reaction at 20-25 °, the reaction mixture was quenched with 15 ml of methanol, diluted with 100 ml of water and basified with concentrated aqueous ammonia to pH = 8 and the reaction product was taken up in chloroform. The crude reaction product was purified by column chromatography on silica gel using benzene +1 ^iO / o ethanol and combined uniform fractions (1.41 g, 58%). Crystallization from chloroform-acetone (1: 1) gave a melting point of 199-200 °; [.alpha.] - 83.4 DEG (c = 0.363).

Example 2

D-2,6-dimethyl-8-ergolin-1-ylacetic acid methyl ester

To a solution of 805.2 mg (2 mmol) of D-6-methyl-2- (1,3-dithiolan-2-yl) -8-ergolin-1-ylacetic acid methyl ester in 5 mL of dimethylformamide and 50 mL of acetone was added 14 ml of Raney nickel suspension and the reaction mixture were vigorously stirred at 20-25 ° for 3 h. After filtering out Raney nickel and evaporating the acetone, the residue was stirred in 200 ml of water, the precipitate was filtered off with suction. washed with water dried. Chromatography of the crude product on a silica gel column using benzene + 2% ethanol gave 468 mg (75%) of a solid which crystallized from chloroform-hexane (1: 3) to give the product, m.p. 220-223 °; [Delta] - 105.7 [deg.] (C = 0.350).

Example 3

D-2,6-dimethyl-8-ergolin-111964 acid amide 4

-ylacetic (maleic acid)

400 mg (1.28 mmol) of D-2,6-dimethyl-8-ergolin-1-ylacetic acid methyl ester was refluxed under a nitrogen atmosphere with 20 ml of 102% hydrazine hydrate. After cooling, the precipitated hydrazide precipitate was filtered off with suction, washed with water and dried (320 mg; 80%) and refluxed with 3 ml of a Raney nickel suspension in 150 ml of 95% ethanol. After filtering off the catalyst and distilling off the ethanol was. the crude reaction product was concentrated and crystallized from benzene-ethanol (2: 1); obtained

Claims (4)

SUBJECT 1. The ergoline-I 2-substituted derivatives of formula I and their pharmaceutically acceptable salts, wherein in formula I, R @ ^{1 is} 1,3-dithiolan-2-yl- or methyl, and R @ ² is alkoxy, with linear or branched alkyl. , containing? 1-4 carbon atoms, or amino. (I). A process for the preparation of 2-substituted ergolin-I derivatives of the general formula I, wherein R ¹ represents 1,3-dithiolan-2-yl α, R ² alkoxy, linear or branched alkyl having 1 to 4 carbon atoms, characterized in that by reacting alkyl esters of D-6-methyl-8-ergolin-1-ylacetic acid containing linear or branched alkyl having 1 to 4 carbon atoms, preferably methyl ester, with 1 to 2 mol equivalents of ethanedithiol and at least 2 mol equivalents of ethyl formate, preferably with an excess thereof, catalytic 203 mg (66.5%) mp 263-265 °; [Α] D = -99.6 ° (c = 0.403). To a boiling solution of 147.8 mg (0.5 mmol) of D-2,6-dimethyl-8-ergolin-1-acetic acid amide in 5 ml of ethanol was added 64 mg (0.55 mmol) of maleic acid and after cooling in the refrigerator, the precipitated salt was aspirated, washed with ether and recrystallized from ethanol; mp 120-124 °; (and)?. - 41.3 ° (c = 0.342). OF THE INVENTION. of 2 to 4 mol equivalents of titanium tetrachloride in an indifferent medium, preferably chloroform, at a temperature ranging from 15 ° C to the boiling point of the reaction mixture, preferably at 20 to 25 ° C, for 1 to 7 days, after which the reaction mixture is worked up in a known way. 3. A process for producing 2-substitution derivatives of ergoline-I, formula I, wherein R ¹ represents a methyl group and R ² an alkoxy group, a linear or branched alkyl containing 1 to 4 carbon atoms, characterized by reacting ester of D -6-methyl-2- (1,3-dithiolan-2-yl) -8-ergolin-1-ylacetic, prepared according to method 2, with Raney nickel in a polar environment, preferably in a mixture of dimethylformamide with acetone, at a temperature of 20 to 25 ° C, for 1 to 24 hours, preferably 3 hours, after which the reaction mixture is worked up in the usual manner. 4. A process for producing 2-substitution derivatives of formula I wherein R ¹ is methyl and R ² is amino, characterized 'in that the reacting ester of D-2,6-dimethyl-ergoline-8-I-ylacetic acid prepared according to item 3, with an excess of hydrazine hydrate, at a temperature of 150 to 160 ° C, after which the resulting D-2,6-dimethyl-8-ergolin-1-ylacetic acid hydrazide is reductively deaminated with Raney nickel in ethanol at the boiling point of the reaction mixture. and the reaction mixture is worked up in the usual manner.